In many age-related neurodegenerative diseases, neuronal loss is correlated with the presence of hyperphosphorylated tau. In Alzheimer's disease, it has been hypothesized that neurons die because cell cycle mechanisms have been activated. In support of this hypothesis, the expression of oncogenes in neurons has caused cell death accompanied by DNA synthesis and the expression of cyclins. In addition, in a fly model for neurodegenerative disease, the death of neurons caused by the expression of hyperphosphorylated human tau could be modulated by cell cycle related proteins. Our laboratory has investigated an interaction between tau and Src family tyrosine kinases and has found that tau can activate these kinases, which are also oncogenes. This application is based on preliminary data showing that hyperphosphorylated tau is present in prostate cancer cells and that tau can potentiate the activation of AP-1, a transcription factor that functions in cell proliferation, survival, and transformation. We propose to use non-neuronal and neuronal cancer cells as model systems to investigate the function of hyperphosphorylated tau in signal transduction mechanisms that control the cell cycle. We will test the hypothesis that tau enhances the activation of AP-1 mediated transcription through its interaction with SFKs, which leads to increased cell proliferation. The specific aims are to (1) determine the role of tau in the regulation of AP-1 activity in cancer cells and (2) determine the effects of tau on cell viability in response to anti-cancer drugs. Resistance to anti-cancer drugs has been correlated with increased levels of tau in breast cancer and we hypothesize that in cancer cells, tau is affecting cell cycle mechanisms, antagonizing the mitotic block caused by the drugs, thereby resulting in drug resistance. In both aims, we will investigate the effects of tau depletion and tau overexpression. Because of the similarities between tau in Alzheimer's disease and tau in prostate cancer cells and the loss of cell cycle control in both age-related diseases, our ultimate aim is to determine if hyperphosphorylated tau is able to tip the balance in cell cycle control mechanisms towards cell division. In so doing, the results of this study will provide a new perspective towards the function of the pre-tangle hyperphosphorylated tau found at the early stages of neurodegenerative disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease and other age-related neurodegenerative diseases is characterized by the presence of brain lesions made of abnormal forms of tau protein. This application will investigate tau in cancer cell lines as we have discovered that this tau has similarities to the abnormal tau in Alzheimer's disease. Moreover, cancer cells have a loss of cell cycle control and a hypothesis in Alzheimer's disease research is that brain cells die because they have lost cell cycle control. The data from this application will further our understanding of how abnormal tau might lead to cell death.